ABSTRACT Hospitalization for acute decompensated heart failure (ADHF) is a significant public health issue and represents a sentinel prognostic event, with high risk of poor clinical outcomes during and after the hospitalization. Investigation to improve the care of ADHF patients is a public health priority. The kidneys have a central role in the acute management and prognosis of ADHF. Kidney injury is highly prevalent in ADHF and is the culmination of hemodynamic alterations, neurohormonal dysregulation, and oxidative stress which cause intra-kidney endothelial damage, inflammation and ischemic injury. Kidney injury is also a key component in decisions of initiation and withdrawal of standard AHDF therapies, which ultimately affects clinical prognosis of ADHF. However, systematic measurement and consideration of kidney injury is not incorporated into algorithms of ADHF therapies, likely due to limitations of current clinically available kidney injury measures. Serum creatinine has traditionally been used to define kidney injury in ADHF, however rises late and is slow to change in response to ongoing kidney injury or repair; which limits its use in dynamic conditions such as ADHF. Studies have shown that serum creatinine is not associated with systemic decongestion or with short-term prognosis in ADHF. Thus, current ADHF guidelines do not endorse serial measures of serum creatinine. The goal of this proposal is to identify novel kidney injury markers that can guide therapy and better determine prognosis in ADHF; thereby improve in-hospital and long-term outcomes. To address this knowledge gap, we propose to conduct a large, prospective study of ADHF patients to determine: (1) if systematic, serial measurements of novel kidney injury markers change in response to a standardized, evidence-based ADHF treatment protocol; (2) and whether these changes are associated with patient-reported, in-hospital and long-term outcomes. Based on previous literature, we have chosen to study a panel of novel kidney injury measures of endothelial injury, inflammation, tubular stress/damage which may better reflect intra-kidney pathophysiology, and may be more dynamic to reflect kidney injury/repair compared with serum creatinine. These novel kidney injury measures are poised to be clinically available in the near future, however are not well studied in ADHF. To support our hypothesis, we conducted a pilot prospective study of 62 patients admitted with ADHF and found that novel kidney injury measures demonstrated greater relative change in response to standardized ADHF therapies and correlated well with systemic congestion; while serum creatinine was relatively static and correlated poorly with systemic congestion. This promising pilot data supports the scientific rationale and feasibility of the proposed work. The data from this study will be used to identify the most promising kidney injury markers in ADHF patients and may be the foundation of future mechanistic studies or a clinical trial to test an ADHF treatment strategy guided by novel kidney injury markers.